Pharmacology I: Lecture 4a - Benzodiazepines

Question 1

What is the structure of benzodiazepines?

Answer 1

Benzodiazepines consist of a benzene ring fused to a seven-membered diazepine ring.

Question 2

What is the mechanism of action of benzodiazepines?

Answer 2

Benzodiazepines bind to the interface of the α and ϒ subunits of the GABAa receptor, increasing opening time of the chloride channel, leading to hyperpolarization of resting potential and potentiating GABAa inhibitory effect.

Question 3

Mechanism of Action Diagram

Answer 3

Question 4

What are some clinical uses of benzodiazepines?

Answer 4

First Clinical Use in 1960, Librium, followed by diazepam

• Anxiolytic
• Sedation
  Insomnia treatment, “sleeping pill”
  ICU usage
  Decrease REM sleep
• Mild muscle relaxation
• Anterograde amnesia
• Panic attacks
• Anticonvulsant
• Restless Leg Syndrome
• Alcohol, benzodiazepine, or opiate withdrawal.

Question 5

Clinical Uses

Answer 5

Replaced barbiturates as sedative

Very effective in the initial management of generalized anxiety disorders, but do not modify the course when used long term

Have been replaced by SSRIs for long term treatment

Also, decline in long term use due to abuse potential and dependence

Alprazolam (Xanax) introduced in 1981 for panic disorders is single most prescribed psychiatric medication
48 million prescriptions annually

Question 6

When was the first benzodiazepine introduced, and what was its name?

Answer 6

The first benzodiazepine, Librium, was introduced in 1960.

Question 7

Clinical Uses for “Anesthesia”

Answer 7

Sedation & anterograde amnesia
Mediated by GABAA – alpha1

Anticonvulsant
Multiple subunits involved

Anxiety – alpha2

Myorelaxation – alpha2

Hypnotic – alpha2

Question 8

Clinical Considerations for all Benzos

Answer 8

Highly bound to plasma proteins

Metabolized by Liver with active metabolites

Important Exceptions: Lorazepam, Oxazepam and Temazepam (LOT) used in patients with liver disease, those that drink a LOT and elderly as they have no active metabolites

Eliminated renally

Synergistic effects with opioids and other sedatives

Question 9

What benzodiazepine is known as the single most prescribed psychiatric medication?

Answer 9

Alprazolam (Xanax) introduced in 1981 for panic disorders. Single most prescribed psychiatric medication = 48 million prescriptions annually

Question 10

True or False: Benzodiazepines have been replaced by SSRIs for long-term treatment of anxiety disorders.

Answer 10

True.

Question 11

What are the important exceptions for benzodiazepines that are safe for patients with liver disease?

Answer 11

Lorazepam, Oxazepam, and Temazepam (LOT).

Have no active metabolites, so have a wider range of patient population they can be administered too.

Question 12

What is the primary concern associated with alprazolam? (Xanax)

Answer 12

It has a high abuse potential.

Question 13

Alprazolam Considerations

Answer 13

Short acting BDZ works on GABAA
Can develop a tolerance

Prescribed to treat anxiety and panic disorders

Sometimes given to chemotherapy patients for nausea

Often concurrently prescribed with patients on amphetamine and dextroamphetamine (Adderall) with high abuse potential

Question 14

What is the pharmacokinetics of alprazolam?

Answer 14

• Absorption: Oral doses peak in 1-2 hours
• Distribution: Highly protein bound
• Metabolism: CYP 450 in the liver to inactive products, no active metabolites… short acting
• Elimination: Renal

Question 15

What are the common dosages for alprazolam?

Answer 15

• 0.25 mg
• 0.5 mg
• 1 mg
• 2 mg

Liquid solutions are rare

Question 16

Complications with Xanax

Answer 16

Synergistic with EtOH and opioids

Often concurrently prescribed with patients on amphetamine and dextroamphetamine (Adderall)

Crosses the placenta, enter into the fetus

Excreted in breast milk
Fatal respiratory depression in children

Use during 3rd trimester
Leads to fetal drug dependence, resp. depression & withdrawal symptoms

Question 17

What is the mechanism of action of lorazepam? (Ativan)

Answer 17

Lorazepam is metabolized in the liver to inactive structures and is safe for liver disease patients.

Enterohepatic recirculation

Safe for Liver Disease patients

Eliminated mainly by kidneys

Question 18

What is the onset and duration of action for lorazepam?

Answer 18

• Onset: 1-2 minutes
• Duration of Action: 6-10 hours.

Question 19

What is the potency/pharmacodynamics of lorazepam compared to versed?

Answer 19

Lorazepam is twice as potent as Versed.

Six times as potent as Valium

Lower lipid solubility
Delayed in crossing BBB
Slower onset of clinical effects
Long DOA (Highly Protein Bound)

Question 20

Clinical Considerations of Ativan

Answer 20

Cardio: ↓SVR, ↓BP

Resp: Ventilatory depression

CNS: ↓CMRO2, ↓CBF, ↓ICP
Agent of choice for status epilepticus

Neuro: Raise seizure threshold

Other:
Patients require smaller and less frequent doses

Question 21

Packaging and Dosing of Lorazepam

Answer 21

Commercial preparation
1 – 2 mg Oral tablets

Dosing
0.5 – 2 mg Oral
Onset 1 – 2 min
DOA 6 – 10 hrs

Question 22

What is the clinical use of diazepam? (Valium)

Answer 22

Diazepam is used as a sedative, anticonvulsant, and muscle relaxant.

Question 23

What is the pharmacokinetics of Diazepam?

Answer 23

Hepatic CYP 450 metabolism to desmethyldiazepam and oxazepam
Active metabolite is Desmethyldiazepam&raquo_space;» oxazepam

Renal elimination
Delayed in elderly, obese, and patients with cirrhosis

Question 24

Pharmacodynamics of Diazepam

Answer 24

Half as potent as versed

One sixth as potent as lorazepam

Desmethyldiazepam can accumulate
Only slight decrease in potency from valium
Long DOA seen

Highly lipid soluble with a large Vd

Question 25

Clinical Considerations of Diazepam

Answer 25

Cardio: mild ↓BP Resp: depressant effects CNS: sedation, anticonvulsant Other: Venous irritant - thrombophlebitis Decreased dose in elderly, severe liver disease, CV unstable Obese require larger initial doses but then have delayed emergence

Question 26

Packaging & Dosing of Diazepam

Answer 26

Commercial preparation 2, 5 & 10 mg/cc Dosing IVP: 2 – 4 mg IV: 0.05 – 0.2 mg/kg Onset: ~ 60 sec DOA: 1 – 6 hrs

Question 27

Structure of Midazolam

Answer 27

Water-soluble with imidazole ring at acidic pH At physiological pH it becomes lipid soluble and rapidly crosses the BBB – access the CNS

Question 28

Pharmacokinetics of Midazolam

Answer 28

Hepatic CYP 450 metabolism Slightly active 1-hydroxymidazolam Renal elimination Renal failure may lead to elevated levels of metabolite and delayed emergence Short term doses – 1.5 to 3.5 hrs Long term infusion – 1.5 to 50 hrs Peripheral tissues become relatively saturated

Question 29

Pharmacodynamics Midazolam

Answer 29

Twice as potent as valium Half as potent as Ativan Emergence from sedation is due to redistribution and clearance Long-term administration – accumulation in peripheral tissues can lead to delayed emergence

Question 30

Clinical Considerations of Versed

Answer 30

Cardio: ↓SVR, ↓BP Resp: ventilatory depression CNS: ↓CMRO2, ↓CBF, ↓ICP, Other: Obese require greater initial dose but this may delay emergence Work synergistically with opioids Exaggerated in the elderly

Question 31

Packaging and Dosing of Midazolam

Answer 31

Commercial preparation 1 or 5 mg/cc Dosing IVP: 1 – 2 mg Induction: 0.2 – 0.3 mg/kg IV: 0.025 – 0.06 mg/kg Onset: ~ 60 sec Peak: 3 – 5 min DOA: 15 – 120 min PO: 0.5 mg/kg Max dose: 20 mg

Question 32

What is the structure of flumazenil? Romazicon

Answer 32

Flumazenil is a 1,4-imidizobenzodiazepine derivative.

Question 33

What is the clinical use of flumazenil?

Answer 33

Flumazenil is used to treat benzodiazepine overdose. Benzodiazepine Antagonist

Question 34

Structure of Flumazenil

Answer 34

1,4 – imidizobenzodiazepine derivative Specific and exclusive benzodiazepine antagonist Competitive Antagonist at GABA BDZ receptor

Question 35

Clinical Considerations of Flumazenil

Answer 35

Used to treat benzodiazepine overdose Complete hepatic metabolism Inactive compounds Renal clearance Most BDZ have longer Duration of Action Re-sedation is possible Multiple doses may be required

Question 36

Packaging and Dosing of Flumazenil

Answer 36

Commercial preparation 0.05 – 0.1 mg/cc flumazenil hydrochloride Dosing IV: 8 – 15 mcg/kg IVP: 0.2 mg q 60 sec until patient responds****IMPORTANT Max dose: 1 – 3 mg Short DOA ~ 20 – 30 min

Question 37

Other Benzo Receptor Ligands

Answer 37

BDZ like Similar benefits & side-effects Differ in chemical structure Lunesta Ambien Sonata Last but not least BDZ you might see is Clonazepam or Klonopin

Question 38

What is a key characteristic of other benzodiazepine receptor ligands?

Answer 38

They have similar benefits and side effects but differ in chemical structure.

Question 39

Fill in the blank: Alprazolam is often prescribed for _______.

Answer 39

[anxiety and panic disorders]

Question 40

What are the potential effects of benzodiazepines during pregnancy?

Answer 40

They can cross the placenta and lead to fetal drug dependence, respiratory depression, and withdrawal symptoms.

Question 41

How does midazolam differ in pharmacodynamics compared to diazepam?

Answer 41

Midazolam is twice as potent as diazepam.